Characterization of Platelet Function in Patients with Bleeding Disorders: In FY2009 (the first year of this project) we have studied several patients with suspected or documented disorders of platelet function and have identified patients with deficiency of dense granules (storage pool disease), and characterized platelet function and protein content people with acquired platelet dysfunction. As we initiate these studies we have defined reference ranges for platelet-derived growth factor, beta-thromboglobulin, and platelet von Willebrand factor in platelet lysates. Future work will focus on measurements of other platelet proteins (e.g., fibrinogen and factor V) so as to have a panel of platelet alpha granule proteins to assess and correlate with bleeding phenotype in congenital or acquired disorders of platelet function. The ability to make a reliable, detailed characterization of platelet function may help investigators who are studying genetics of inherited platelet disorders. Characterization of D-Dimer and Related Coagulation Proteins in HIV-Infected Research Subjects Undergoing IL-2 Therapy: During the first year of this project, in support of intramural NIH research protocols, we have measured D-dimer levels on archived plasma samples from HIV-infected research subjects on anti-retroviral intervention with interleukin 2 (IL-2). We observed that D-dimer levels increased with IL-2 therapy, positively correlating with increases in C-reactive protein levels and greater pre-IL-2 HIV viremia. In HIV-infected patients with osteonecrosis, D-dimer levels were higher at the time of diagnosis than for HIV-infected patients without osteonecrosis (but not at other time points). Future work will consist of a prospective study of 160 HIV positive and 40 HIV negative controls to determine whether the correlation between D-dimer and all-cause mortality corresponds to viral burden, various cytokines, or other paramters under study. Markers of Endothelial Cell Injury and Thrombosis in Patients Undergoing Cancer Chemotherapy. During the second year of this project, in support of intramural NIH research protocols, we measured various markers of thrombosis (prothrombin fragment 1.2, D-dimer, thrombin-antithrombin complexes, tissue factor, sVCAM, thrombomodulin, E-selectin, etc.) in chronic lymphocytic leukemia (CLL) that were treated with the thalidomide derivative revlimid. Some of these patients developed DVT while on the study, and the preliminary findings are that thrombomodulin and sVCAM elevations correspond to TNFalpha cytokine elevations in the patients with DVT. In the future we will seek to characterize the nature of the endothelial damage by assessment of related endothelial markers and also to look for other signs of abnormal hemostasis in treated patients with revlimid.